Poxel Presents Promising Data for PXL770 and PXL065 for the Treatment of NASH at the American Association for the Study of Liver Diseases Meeting

PXL770 was shown to have a beneficial effect on both the adipose
tissue and liver through direct activation of AMPK in a DIO-NASH model

PXL065 data suggests the potential for similar efficacy with a
reduced side effect profile from pioglitazone for NASH

LYON, France--(BUSINESS WIRE)--
POXEL
SA (Euronext: POXEL - FR0012432516), a biopharmaceutical company
focused on the development of innovative treatments for metabolic
disorders, including type 2 diabetes and non-alcoholic steatohepatitis
(NASH), today announced that poster presentations for PXL770 and PXL065
(formerly DRX-065; acquired from DeuteRx LLC) showing promising data for
the treatment of NASH were made on November 10-11, 2018, at the American
Association for the Study of Liver Diseases (AASLD) meeting in San
Francisco, California.

In the first poster presentation, PXL770 was shown to have a beneficial
effect on the two key pathways involved in non-alcoholic fatty liver
disease (NAFLD), the lipolysis in the adipose tissue (AT) and de novo
lipogenesis in the liver, through direct activation of adenosine
monophosphate-activated protein kinase (AMPK) in a diet-induced obesity
non-alcoholic steatohepatitis (DIO-NASH) model. NAFLD is characterized
by hepatic lipid accumulation resulting primarily from AT lipolysis
(70%), and de novo lipogenesis (20%), highlighting the key role
of AT in the development of NAFLD.

“AMPK is a key target acting on steatosis, inflammation and hepatic
fibrogenesis,” said Sophie Bozec, PhD, Senior Vice President, Research
and Development Pharmacology at Poxel. “Supported by positive
preclinical mechanistic and efficacy results in a DIO-NASH model, we
believe that PXL770 is uniquely positioned to treat the underlying root
causes of NASH, including liver steatosis, inflammation and fibrosis,
which are driven by the accumulation of free fatty acids in the liver
coming from the AT and from their endogenous synthesis in the liver.”

In the second poster presentation, PXL065 Phase 1 results demonstrated
that PXL065 was shown to be safe and well-tolerated with no adverse
events. Based on the pharmacokinetic (PK) results, modeling predicts
that a 15 mg dose of PXL065, a deuterium-stabilized R-stereoisomer of
pioglitazone, is expected to yield similar efficacy as 45 mg of the
parent drug, pioglitazone (Actos®*) with an improved side
effect profile, including reduced weight gain and fluid retention.

“Pioglitazone has demonstrated therapeutic efficacy for NASH, even in
patients with advanced fibrosis. However, its PPARγ-related side effects
of weight gain, bone fractures and fluid retention have limited its
therapeutic potential and use,” said Pascale Fouqeray, MD, PhD, EVP,
Early Development and Translational Medicine at Poxel. “PXL065 has the
potential to preserve the pharmacological benefits of pioglitazone
required for the treatment of NASH, such as a reduction of hepatic
steatosis, inflammation, ballooning and fibrosis and could reduce PPARγ
agonism and the associated side effects that are thought to be related
to S-pioglitazone.”

“We are looking forward to advancing both PXL770 and PXL065 into
proof-of-concept studies in 2019,” said Thomas Kuhn, CEO of Poxel. “With
the recent acquisition of DeuteRx’s drug candidate, PXL065, we are
rapidly expanding our presence in NASH and are one of only a few biotech
companies with two clinical programs in development in this therapeutic
area. The underlying pathophysiological mechanisms that contribute to
the development and progression of NAFLD and NASH are highly complex and
support the need for the development of novel therapies acting on
different targets. Both of our programs have the potential to be
developed as a monotherapy or in combination together or with other
agents.”

PXL770 Results

In the poster presentation, PXL770 was shown to have a beneficial effect
on the liver and AT metabolism in a DIO-NASH mouse model. After 41
weeks, only DIO-NASH mice with biopsy-confirmed steatosis (score ≥2) and
fibrosis (stage ≥1) were included (n=12) and received orally vehicle
(control) or PXL770 35 or 75 mg/kg twice-daily for eight weeks.

Based on these and other preclinical findings, PXL770 appears to be a
promising drug candidate for the treatment of NASH.

PXL065 Results

In the poster presentation for PXL065, a Phase 1 open-label study was
presented, which evaluated the safety, tolerability and pharmacokinetics
(PK) of a single dose of PXL065 compared to Actos®, in
healthy subjects. Twelve healthy subjects received a single oral dose of
45 mg Actos or 22.5 mg PXL065. Subjects remained in the clinic for 36
hours post-dose and returned as out-patients on Days 4 and 7 for
follow-up assessments. Based on these results, a PK model was generated
to predict the dose of PXL065 that gives the same exposure to
R-pioglitazone as a 45 mg dose of Actos and the number of dosing days
required to reach steady state. In addition, exposure to PPARγ active
species was compared between equivalent doses of PXL065 and Actos.

The Phase 1 study indicated PXL065 was safe and well-tolerated. No
adverse effects were reported. After a single dose of PXL065, the
relative exposure to R-pioglitazone increased >3-fold compared to Actos.
Total exposure to the PPARγ active metabolites, M-III and M-IV,
decreased by 50% compared to Actos.

Based on modeling, a 15 mg dose of PXL065 is predicted to yield the same
exposure to R-pioglitazone as a 45 mg dose of Actos. The human PK
results and simulations, combined with preclinical animal studies,
suggest that PXL065, has the potential to offer similar efficacy for
NASH compared to pioglitazone with a reduction of the undesired
PPARγ-related side effects of weight gain and fluid retention.

The posters titled “PXL770, a New Direct AMP Kinase Activator, Acting on
the Adipose Tissue and the Liver, Demonstrates Promising Effects for
Treatment of Non-Alcoholic Steatohepatitis” and “Safety, Tolerability
and Pharmacokinetics of PXL065, the Stabilized, R-Stereoisomer of
Pioglitazone: A Mitochondrial Function Modulator for Nonalcoholic
Steatohepatitis (NASH) without the PPARγ Agonism and Related Side
Effects” are available on the Company’s website under “Posters” or by
using the following link http://www.poxelpharma.com/en_us/product-pipeline/posters.

About NASH

Non-alcoholic steatohepatitis (NASH) is a metabolic disease with no
clear disease origin that is quickly becoming a worldwide epidemic. It
is characterized by the accumulation of fat in the liver causing
inflammation and fibrosis. The disease can be silent for a long period
of time, but once it accelerates, severe damage and liver cirrhosis can
occur, which can significantly impact liver function or can even result
in liver failure or liver cancer. Typical risk factors for NASH include
obesity, elevated levels of blood lipids (such as cholesterol and
triglycerides) and diabetes. Currently no curative or specific therapies
are available.

About PXL770

PXL770 is a first-in-class direct adenosine monophosphate-activated
protein kinase (AMPK) activator. AMPK is a central regulator of multiple
metabolic pathways leading to the control of lipid metabolism, glucose
homeostasis and inflammation. Based on its central metabolic role,
targeting AMPK offers the opportunity to pursue a wide range of
indications to treat chronic metabolic diseases, including diseases that
affect the liver, such as non-alcoholic steatohepatitis (NASH)1.

About PXL065 (formerly DRX-065)

PXL065 is deuterium-stabilized R-pioglitazone developed by DeuteRx LLC.
Pioglitazone is the most extensively studied drug for NASH and has
demonstrated “resolution of NASH without worsening of fibrosis” in a
Phase 4 trial2. Pioglitazone is the only drug recommended for
biopsy-proven NASH patients by the Practice Guidelines published by the
American Association for the Study of Liver Diseases (AASLD) and the
European Association for the Study of the Liver (EASL).3 Pioglitazone’s
use for NASH, however, has been limited due to the PPARγ-related side
effects, which include weight gain, bone fractures and fluid retention.

Pioglitazone is a 1:1 mixture of two mirror-image compounds
(stereoisomers) that interconvert in vivo. Using deuterium,
DeuteRx stabilized each stereoisomer and characterized their
dramatically different pharmacological properties. In in vitro studies,
PXL065 has been shown to target MPC as an inhibitor. In preclinical
models, PXL065 exhibits the anti-inflammatory activity and NASH efficacy
associated with pioglitazone with little or no weight gain or fluid
retention, side effects which are associated with the S-stereoisomer.
Based upon preclinical and Phase 1 results to date, PXL065 is expected
to exhibit a better therapeutic profile than pioglitazone for NASH.

About Poxel SA

Poxel uses its development expertise in metabolism to advance a pipeline
of drug candidates focused on the treatment of metabolic disorders,
including type 2 diabetes and non-alcoholic steatohepatitis (NASH). We
have successfully completed the Phase 2 clinical program for our
first-in-class lead product, Imeglimin, which targets mitochondrial
dysfunction, in the U.S., Europe and Japan. Together, with our partner
Sumitomo Dainippon Pharma, we are conducting the Phase 3 Trials of
IMeglimin for Efficacy and Safety (TIMES) program for the treatment of
type 2 diabetes in Japan. Our partner Roivant Sciences is responsible
for Imeglimin’s development and commercialization in countries outside
of Poxel’s partnership with Sumitomo Dainippon Pharma, including the
U.S. and Europe. PXL770, a first in class direct adenosine
monophosphate-activated protein kinase (AMPK) activator, is advancing
into a Phase 2a proof-of-concept program for the treatment of NASH.
PXL770 could also have the potential to treat additional metabolic
diseases. PXL065 (deuterium-stabilized R-pioglitazone), a mitochondrial
pyruvate carrier (MPC) inhibitor, is in Phase 1 and being developed for
the treatment of NASH. Poxel also has additional earlier-stage programs,
including deuterated drug candidates for metabolic, specialty and rare
diseases. We intend to generate further growth through strategic
partnerships and pipeline development. (Euronext: POXEL, www.poxelpharma.com)